Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC.
Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC.
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DOI：
10.1038/srep23608
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发表时间：
2016-03-23
影响因子：
4.6
通讯作者：
Mishra S
中科院分区：
文献类型：
--
作者：
Ande SR;Nguyen KH;Grégoire Nyomba BL;Mishra S
肥胖会增加非酒精性脂肪性肝炎（NASH）和肝癌发生的风险。然而，疾病过程中涉及的潜在机制仍不清楚。最近，我们建立了一个转基因肥胖小鼠模型（Mito-Ob）通过抑制素介导的脂肪细胞线粒体重塑。Mito-Ob小鼠以性别中性的方式发展肥胖，但以雄性性别特异性的方式发展肥胖相关的脂肪炎症和代谢失调。在这里，我们报告说，随着年龄的增长，雄性Mito-Ob小鼠自发发展肥胖相关的NASH和肝细胞癌（HCC）。相比之下，雌性Mito-Ob小鼠保持正常的葡萄糖和胰岛素水平，并且没有发展NASH和HCC。与相应的对照小鼠相比，抗炎肽ghrelin在雌性小鼠中显著上调，在雄性小鼠中下调。此外，在患有NASH/HCC的雄性Mito-Ob小鼠的肝脏中发现线粒体含量和功能标志物的减少。我们发现在Mito-Ob小鼠的肿瘤中，ERK 1/2信号显著上调，而STAT 3信号显著下调。这些数据提供了一个概念验证，即脂肪组织的代谢和炎症状态及其在全身和肝脏水平的相互作用在肥胖相关NASH和HCC的发病机制中起着核心作用。
Obesity increases the risk for nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. However, the underlying mechanisms involved in the disease process remain unclear. Recently, we have developed a transgenic obese mouse model (Mito-Ob) by prohibitin mediated mitochondrial remodeling in adipocytes. The Mito-Ob mice develop obesity in a sex-neutral manner, but obesity-associated adipose inflammation and metabolic dysregulation in a male sex-specific manner. Here we report that with aging, the male Mito-Ob mice spontaneously develop obesity-linked NASH and hepatocellular carcinoma (HCC). In contrast, the female Mito-Ob mice maintained normal glucose and insulin levels and did not develop NASH and HCC. The anti-inflammatory peptide ghrelin was significantly upregulated in the female mice and down regulated in the male mice compared with respective control mice. In addition, a reduction in the markers of mitochondrial content and function was found in the liver of male Mito-Ob mice with NASH/HCC development. We found that ERK1/2 signaling was significantly upregulated whereas STAT3 signaling was significantly down regulated in the tumors from Mito-Ob mice. These data provide a proof-of-concept that the metabolic and inflammatory status of the adipose tissue and their interplay at the systemic and hepatic level play a central role in the pathogenesis of obesity-linked NASH and HCC.